First-Ever Randomized Trial Shows Oral Insulin Feasibility

Oral insulin isn't available just yet, but proof of its feasibility has now been published for the first time, with the results of a randomized, controlled clinical trial in patients with type 2 diabetes.

Findings from the phase 2 trial of Novo Nordisk's investigational — and now discontinued — long-acting oral basal insulin "I338" were published online January 21 in Lancet Diabetes & Endocrinology by Inge B. Halberg, PhD, of the company, and colleagues.

The product was formulated in a tablet with the absorption enhancer sodium caprate to make it less susceptible to degradation in the gastrointestinal tract. Sodium caprate is the sodium salt of the fatty acid caprate, which is approved as a food additive and considered safe by the US Food and Drug Administration.

In the study, which involved 50 insulin-naive patients with type 2 diabetes, oral I338 reduced fasting plasma glucose (FPG) at 8 weeks — similarly to injected insulin glargine — with no significant differences in adverse events. Novo Nordisk is no longer pursuing the I338 formulation because the effective doses were too high and production required quantities deemed not commercially viable.

Nonetheless, the proof-of-concept is "likely to encourage the further development of oral insulin products to the benefit of patients with diabetes," Halberg and colleagues write.

They point out that beyond the potential for better patient adherence because of the avoidance of injections other advantages of oral insulin include more physiologic insulin delivery via the portal vein directly to the liver, potentially reducing weight gain and hypoglycemia.

In an accompanying editorial, Chantal Mathieu, MD, PhD, professor of medicine at the Katholieke Universiteit Leuven, and chair of endocrinology at the University Hospital Gasthuisberg, Leuven, Belgium, expressed excitement over the findings, writing, "The conclusion on the present study should be a positive one: history is being written!"

In agreement with the company's decision not to continue development of I338, Mathieu cited both its dose issue and variability. But, she concluded, "Oral insulin is a reality and although the present formulation will not be the one taken forward, Halberg and colleagues have blazed a trail and have provided hope for those who need insulin but delay its use because it needs to be injected."

No Difference Compared With Injected Glargine

In the two-center study, the results of which were first reported by Medscape Medical News at the American Diabetes Association (ADA) 2017 Scientific Sessions, 50 patients who hadn't achieved optimal glycemic control (HbA_1c 7.0%-10.0%) with metformin alone or combined with other oral glucose-lowering drugs were randomized to I338 plus sham injection or insulin glargine injection plus placebo tablet. Doses were titrated to achieve a self-measured FPG of 4.4-7.0 mmol/L (79-126 mg/dL).

From baseline to 8 weeks, mean changes in FPG — the primary endpoint — were not significantly different: a drop of 2.4 mmol/L (43 mg/dL) with I338 and 2.6 mmol/L (47 mg/dL) with glargine (P = .46 for treatment difference).

Estimated mean change in HbA_1c from baseline to 8 weeks was not significantly different either — a decrease of 0.75 percentage points with I338 versus a drop of 1.05 with glargine (P = .077 for treatment difference).

Adverse event rates were similar between the two groups, with most being mild and assessed as unlikely to be related to the trial product. Hypoglycemia rates were low in both groups — 7 with I338 versus 11 with glargine — and there were no serious hypoglycemic events.

Clever Approach: Long-Acting Formulation May Be Key to Success

Mathieu noted, "Since the early days of insulin therapy, reports on oral formulations have been presented, but never has a formulation reached a development stage in a way that holds promise for actual clinical application."

Part of the reason for the success of I338, both she and the study authors point out, is that it was designed as a long-acting basal insulin rather than a pre-meal insulin.

"The few clinical experiences with other oral insulin products might be due to the fact that all previous oral insulin products have been short-acting insulin formulations given at mealtimes," Halberg and colleagues write.

These present "greater challenges than for a basal oral insulin due to the potential effect of food on insulin absorption after oral administration," they note.

Indeed, Mathieu says, "The cleverness of the approach...lies in the fact that they have exploited their technology for prolongation, of insulin action, as has been used in other insulins, such as insulin detemir and insulin degludec, namely through binding to circulating albumin," and thereby "moved away from the old concept that oral insulin would be an ingested mealtime insulin."

But, she cautioned, there were still downsides with the formulation — the need to ingest it after fasting for at least 30 minutes and the need to still titrate and self-monitor, among other issues.

And noting that inhaled insulin had been hailed as a potential answer to the fact that patients don't like to inject insulin, but it "failed in most areas of the world and is used rarely nowadays," she says it is therefore "very important to clearly communicate that oral insulin is emerging as a potential treatment, but it will not be the wonder pill to ingest once daily and allow patients to forget all about their diabetes."

The study was funded by Novo Nordisk, and three of the authors including Halberg are employees and shareholders. Mathieu has served on advisory panels and/or speakers bureaus for Novo Nordisk, Sanofi, Merck Sharp and Dohme, Eli Lilly, Novartis, AstraZeneca, Boehringer Ingelheim, Hanmi Pharmaceuticals, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Dianax, and Union Chimique Belge.

Lancet Diabetes & Endocrinol. Published online January 21, 2019. Abstract, Editorial

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